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Synthetic Methods of Phosphonopeptides

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Synthetic Methods of Phosphonopeptides molecules Review Synthetic Methods of Phosphonopeptides Jiaxi Xu State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, College of Chemistry, Beijing University of Chemical Technology, Beijing 100029, China; [email protected]; Tel./Fax: +86-10-6443-5565 Academic Editors: Graeme Barker and Simona Rapposelli Received: 8 November 2020; Accepted: 10 December 2020; Published: 12 December 2020 Abstract: Phosphonopeptides are phosphorus analogues of peptides and have been widely applied as enzyme inhibitors and antigens to induce catalytic antibodies. Phosphonopeptides generally contain one aminoalkylphosphonic acid residue and include phosphonopeptides with C-terminal aminoalkylphosphonic acids and phosphonopeptides with a phosphonamidate bond. The phosph- onamidate bond in the phosphonopeptides is generally formed via phosphonylation with phosphonochloridates, condensation with coupling reagents and enzymes, and phosphinylation followed by oxidation. Pseudo four-component condensation reaction of amides, aldehydes, alkyl dichlorophosphites, and amino/peptide esters is an alternative, convergent, and efficient strategy for synthesis of phosphonopeptides through simultaneous construction of aminoalkylphosphonic acids and formation of the phosphonamidate bond. This review focuses on the synthetic methods of phosphonopeptides containing a phosphonamidate bond. Keywords: phosphonamidate; phosphonopeptide; β-phosphonopeptide; γ-phosphonopeptide; peptide 1. Introduction Phosphonopeptides are phosphorus analogues of peptides. They generally contain one aminoalkylphosphonic acid residue and include phosphonopeptides with C-terminal aminoalkylph- osphonic acids and phosphonopeptides containing a phosphonamidate bond [1,2]. Phosphonopeptides have been used as antibacterial agents [3]. They have been widely applied as enzyme inhibitors [4–8] and antigens for inducing catalytic antibodies [9–12] due to their tetrahedral structural feature. Phosphonopeptides containing C-terminal aminoalkylphosphonic acids have been prepared via coupling of N-protected amino acyl chlorides with aminoalkylphosphonic acids [13], condensation of N-protected amino acids or peptides and aminoalkylphosphonic acids with coupling reagents [14,15], aminolysis of N-chloroacetyl aminoalkylphosphonic acids [16], and the Mannich-type reactions of N-protected amino amides or aminoalkanesulfonamides, aldehydes, and phosphorus trichloride followed by hydrolysis [17,18]. Synthesis of phosphonopeptides with C-terminal aminoalkylphosphonic acids was reviewed recently [19]. This review focuses on the synthetic methods of phosphonopeptides, including α-, β-, γ-, and δ-phosphonopeptides (Figure1), with a phosphonamidate bond, especially focuses on the synthetic strategies for the formation of the phosphonamidate bond, excluding the modification of phosphonopeptides. Molecules 2020, 25, 5894; doi:10.3390/molecules25245894 www.mdpi.com/journal/molecules Molecules 2017, 22, x 2 of 23 Molecules 2020, 25, 5894 2 of 21 Molecules 2017, 22, x 2 of 23 Figure 1. Different classes of phosphonopeptides. Figure 1. DifferentDifferent classes of phosphonopeptide phosphonopeptides.s. 2. Synthesis of Phosphonopeptides via Phosphonochloridates 2. Synthesis of Phosphonopeptides via Phosphonochloridates 2. SynthesisPhosphonylation of Phosphonopeptides of amino/peptide via Phosphonochl oestersridates with alkyl N-protected Phosphonylation of amino/peptide esters with alkyl N-protected aminoalkylphosphonochloridates aminoalkylphosphonochloridatesPhosphonylation of isamino/peptide a general and widelyesters appliedwith method alkyl for the synthesisN-protected of is a general and widely applied method for the synthesis of phosphonopeptides containing a aminoalkylphosphonochloridatesphosphonopeptides containing a isphosphonamidate a general and widelybond. Theapplied phosphonochloridates method for the synthesis are usually of phosphonamidate bond. The phosphonochloridates are usually prepared via chlorination of the phosphonopeptidesprepared via chlorination containing of the correspondinga phosphonamidate dialkyl bond. phosph Theonates phosphonochloridates with phosphorus pentachloride are usually corresponding dialkyl phosphonates with phosphorus pentachloride [13,20] or phosphorus prepared[13,20] or viaphosphorus chlorination oxychloride of the corresponding [21], chlorination dialkyl of phos phosphonicphonates monoesters with phosphorus with thionyl pentachloride chloride oxychloride [21], chlorination of phosphonic monoesters with thionyl chloride [22,23] or oxalyl [13,20][22,23] oror phosphorusoxalyl chloride oxychloride [24,25], and [21] chlorination, chlorination of of alkyl phosphonic trimethylsilyl monoesters phosphonates with thionyl [26] chloride or alkyl chloride [24,25], and chlorination of alkyl trimethylsilyl phosphonates [26] or alkyl phosphinates [27] [phosp22,23]hinates or oxalyl [27] chloride with [2carbon4,25], and tetrachloride chlorination. Phosphonobromidatesof alkyl trimethylsilyl phosphonates are seldom [26]applied or alkyl as with carbon tetrachloride. Phosphonobromidates are seldom applied as intermediates in the synthesis phospintermediateshinates [27]in the with synthesis carbon of tetrachloridephosphonopeptides. Phosphonobromidates and generated viaare brominationseldom applied of alkyl as of phosphonopeptides and generated via bromination of alkyl phosphinates with bromine [28]. Each of intermediatesphosphinates within the bromine synthesis [28] of. Eachphosphonopeptides of the above- mentionedand generated methods via brominationwill be presented of alkyl as the above-mentioned methods will be presented as following. phosphinatesfollowing. with bromine [28]. Each of the above-mentioned methods will be presented as following. 2.1. Chlorination of D Dialkylialkyl PhosphonatesPhosphonates with PhosphorusPhosphorus PentachloridePentachloride 2.1. ChlorinationAfter aminomethylphosphonic aminomethylphosphonic of Dialkyl Phosphonates acid acid with was P washosphorus isolated isolated P fromentachloride from numerous numerous organisms organisms and andanimal animal and and human organs [29,30], to understand the biological significance of this new class of compounds, humanAfter organs aminomethylphosphonic [29,30], to understand acid the was biological isolated significance from numerous of this org newanisms class and of compounds,animal and phosphonodipeptide was synthesized in 1973. Diisopropyl N-phthalyl(Phth)aminomethylphosphonate humanphosphonodipeptide organs [29,30] , to understandwas synthesizedthe biological significancein of1973. this new Diisoproclass of pcompounds,yl N- was prepared from phthalylaminomethyl chloride and triisopropyl phosphite and further phosphonodipeptidephthalyl(Phth)aminomethylphosphonate was synthesized was prepared infrom phthalylaminomethyl1973. Diisopro chlorpyl ide andN- treated with phosphorus pentachloride to give the corresponding isopropyl N-phthalylaminome phthalyltriisopropyl(Phth) phosphiteaminomethylphosphonate and further treated waswith preparedphosphorus from pentachloride phthalylaminomethyl to give the correspondingchloride and thylphosphonochloridate, which reacted with ethyl glycinate in the presence of triethylamine to triisopropylisopropyl N phosphite-phthalylaminomethylphosphonochloridate, and further treated with phosphorus which pentachloride reacted with to give ethyl the glycinate corresponding in the give rise to protected phosphonopeptide (Scheme1)[ 13]. This is the first chemical synthesis of isopropylpresence of N triethylamine-phthalylaminomethylphosphonochloridate, to give rise to protected phosph owhichnopeptide reacted (Scheme with ethyl1) [13]. glycinate This is the in firstthe α-phosphonopeptide with a phosphonamidate linkage. presencechemical ofsynthesis triethylamine of α-phosphonopeptide to give rise to protected with a pho phosphonamidatesphonopeptide (Schemelinkage. 1) [13]. This is the first chemical synthesis of α-phosphonopeptide with a phosphonamidate linkage. Scheme 1. First synthesis of phosphonopeptide. Scheme 1. First synthesis of phosphonopeptide. Similarly, N-phthalylaminomethylphosphonochloridateScheme 1. First synthesis of phosphonopeptide was prepared. and further coupled withSimilarly, dipeptide N esters-phthalylaminomethylphosphonochloridate to afford phosphonotripeptides. After was hydrazinolysis prepared and and further acetylation coupled with aceticdipeptideSimilarly, anhydride esters N -andtophthalylaminomethylphosphonochloridate afford acylation phosphonotripeptides. with acyl chlorides or AfterN-benzyloxycarbonyl(Cbz)-protected hydrazinolysis was prepared and and acetylation further coupled dipeptides,with acetic with dipeptidetheanhydride phosphonotripeptides esters and acylation to afford with werephosphonotripeptides. acyl transformed chlorides or into N-N benzyloxycarbonyl(After-acetyl hydrazinolysis phosphonotripeptides,Cbz and)-protected acetylationN-acyl dipeptides, with phosphono acetic the anhydridetripeptides,phosphonotripeptides and and acylation phosphonopentapeptides withwere acyl transformed chlorides after or hydrogenolysis,N-intobenzyloxycarbonyl( N-acetyl respectively phosphCbz)-protectedo (Schemenotripeptides,2 ).dipeptides, As inhibitors N-acyl the phosphonotripeptidesofphosphonotripeptides enkephalinase and , angiotensin-convertingandwere phosphonopentapeptides transformed enzymeinto afterN (ACE),-acetyl hydrogenolysis, these phosph phosphonopeptideso respectivelynotripeptides, (Scheme exhibitedN-acyl 2). phosphonotripeptidesAs
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